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Effectiveness of Pseudoephedrine Plus Acetaminophen for Treatment of Symptoms Attributed to the Paranasal Sinuses Associated With the Common Cold
Steven J. Sperber, MD;
Ronald B. Turner, MD;
James V. Sorrentino, PhD;
Robert R. O'Connor, BS;
James Rogers, PhD;
Jack M. Gwaltney, Jr, MD
Arch Fam Med. 2000;9:979-985.
ABSTRACT
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Background Little data exist on the cause and treatment of subfacial pain and pressure and other discomfort attributed to the paranasal sinuses that develop early during the course of the common cold. The purpose of this study was to determine the efficacy of the combination of pseudoephedrine hydrochloride with acetaminophen for the treatment of early symptoms during colds, which are attributed by the patient to the sinuses.
Methods Four hundred thirty subjects (216, pseudoephedrine and acetaminophen recipients; 214, placebo recipients) with cold symptoms of 48 hours or less who reported overall "sinus" symptoms of at least moderate severity were enrolled in this randomized double-blind placebo-controlled 2-dose study. Self-reported symptoms were scored (0 to 4, absent to severe) before and at 2 hours after the first and second doses. The 2 primary were measured 2 hours after the second dose were the overall sinus symptom assessment and a weighted composite assessment of sinus pressure, pain, and congestion (sinus symptoms).
Results Compared with baseline, 2 hours after the second dose, the mean ± SEM overall sinus symptom assessment score had decreased by 1.30 ± 0.06 in the pseudoephedrine and acetaminophen–treated subjects compared with 0.93 ± 0.06 in the placebo-treated subjects (P .029). The mean ± SEM weighted average of sinus symptoms 2 hours after the second dose of study medication had decreased by 1.14 ± 0.06 in the pseudoephedrine and acetaminophen–treated subjects compared with 0.84 ± 0.06 in the placebo-treated subjects (P.029). Reductions in similar magnitude were also observed for each of the individual sinus symptoms, and headache and rhinorrhea. Nervousness occurred in 4% of the pseudoephedrine and acetaminophen recipients compared with 0% of placebo recipients (P = .007).
Conclusion Our results suggest that pseudoephedrine plus acetaminophen is effective for relief of symptoms attributable to the paranasal sinuses that may develop early in the course of a cold.
INTRODUCTION
THE COMMON cold remains the most prevalent cause of acute morbidity in the United States. More than $1 billion is spent annually in the United States on various cold therapies.1 For the most part, these involve over-the-counter symptomatic treatment of cold symptoms. Cold sufferers frequently use such therapies for the relief of symptoms that they attribute to involvement of the paranasal sinuses. A 1996 study revealed that approximately one half of adult consumers surveyed used over-the-counter cold remedies to alleviate a "sinus condition" consisting of pain, pressure, and congestion (R.R.O., data on file, Novartis Consumer Health Inc, Summit, NJ, October 1996). The pathophysiologic events leading to the development of these symptoms are not well understood. Common colds affect the upper nasal passages, especially the osteomeatal complex. Using reverse transcription polymerase chain reaction, rhinovirus RNA has recently been detected in 40% of maxillary aspirates of patients with acute sinusitis.2 Also, abnormalities of the paranasal sinuses have been demonstrated by computed tomography in more than 85% of adults early in the course of naturally acquired colds, leading to the conclusion that the common cold is a "viral rhinosinusitis."3
Previous studies have demonstrated beneficial effects of oral decongestants, which are  -adrenergic agonists, alone4-7 or in combination with antihistamines,5, 8-10 anticholinergic agents,11 or nonsteroidal antiinflammatory drugs12-13 on a variety of symptoms and/or objective measures in natural and experimentally induced colds. Prior studies of treatment of the common cold have not focused specifically on the relief of symptoms perceived by the patient to be due to the sinuses. The purpose of this study was to determine the efficacy of the combination of pseudoephedrine hydrochloride with acetaminophen for the treatment of early symptoms attributed to the paranasal sinuses in subjects with natural colds. Subjects were preselected for the specific symptoms being studied, and efficacy was assessed over a short time course of only 8 hours, reflecting 2 doses of study medication.
SUBJECTS, MATERIALS AND METHODS
SUBJECTS
Men and women aged 18 to 65 years were recruited during December 1996 to May 1997 at 3 study sites: the University of Virginia, Charlottesville; Hackensack University Medical Center, Hackensack, NJ; and the Medical University of South Carolina, Charleston. The protocol was approved by the Institutional Review Boards at the respective institutions, and all subjects gave written informed consent for participation. Subjects were eligible to participate if they were otherwise healthy, had cold symptoms of 48 hours' or less duration, and reported at least moderate symptom severity in response to the question, "Overall, how would you rate the severity of your sinus symptoms? Absent, mild, moderate, moderately severe, or severe." The subjects were blinded to the inclusion criteria and primary outcome measures. Women of childbearing age were required to have negative results from a pregnancy test and use effective birth control. Subjects whose diastolic blood pressure was greater than 90 mm Hg at the time of screening were also excluded. Subjects with underlying illnesses that might be exacerbated by sympathomimetic drugs or that might affect the assessment of common cold symptoms were excluded from the study. Subjects who were receiving medications that might interact with sympathomimetic drugs were also excluded from the study. Subjects received financial compensation for their participation.
STUDY MEDICATIONS
Study subjects were randomly assigned to receive bottles containing either 60 mg of pseudoephedrine plus 1000 mg of acetaminophen or identically appearing placebo tablets. The initial dose of study medication was administered by a study nurse between 8 AM and 11 AM. The second dose was self-administered 6 hours after the first dose. Empty bottles were collected to confirm that all medications had been received. Subjects were instructed not to undergo any other common cold treatment while in the study.
STUDY PROCEDURES
The study was a randomized, double-blind, placebo-controlled clinical trial. Prior to the first dose of study medication, baseline symptom evaluations were made using a symptom severity scale of 0 to 4, corresponding to absent, mild, moderate, moderately severe, and severe. The symptoms rated were overall nasal symptom assessment, sneezing, runny nose, nasal obstruction (stopped-up nose), overall sinus symptom assessment, sinus pain, sinus pressure, sinus congestion, overall throat symptom assessment, sore throat, cough, headache, and malaise. These symptom assessments were made by the subjects based on their self-perception of symptom type and location. Height and weight were recorded. Subjects were instructed to contact the study site 2 hours after taking each dose of study medication. The symptoms and severity scale used in these assessments were the same as those used for the baseline evaluation. If the 2-hour postdose symptom evaluations could not be made interactively with the study staff, the subject recorded his or her assessments to the questions in writing in a diary that had been provided for this purpose. Most of the assessments were performed interactively with the study staff (81% after the first dose and 72% after the second dose). Subjects were told to avoid concomitant medication during the 8-hour study period. If administration of concomitant medications was unavoidable, such administration was to be recorded in the study diary. Subjects were to record in their diaries the occurrence of any adverse effect. Each subject reported to the study site 18 to 48 hours after receiving the second dose of study medication. Study diaries were returned and reviewed, and study medication bottles were returned.
DATA ANALYSIS
Demographic data and symptom severity were compared to document similarity of the treatment groups at baseline. A 1-way analysis of variance was used to compare data for age, height, weight, and baseline symptoms. The Fisher exact test was used for comparison of sex and race and for the safety analysis.
The primary analysis for the efficacy of pseudoephedrine and acetaminophen included 2 variables, each evaluated 2 hours after the second dose. These outcome measures included an overall sinus symptom assessment and a composite score reflecting assessment of sinus pressure, pain, and congestion. The composite score was computed using an a priori rule specifying that the proportions of subjects with at least moderately severe sinus pain (23%), sinus pressure (30%), and sinus congestion (45%) were to serve as weights. These weights were adjusted so that their sum was equal to 1.0. The composite sinus score and overall sinus symptom assessment 2 hours after the first dose of study medication as well as various other variables were considered to be secondary.
All available data, including data from subjects who withdrew from the study after receiving at least 1 dose of study medication, were included in the analysis. Intent-to-treat analyses were performed for efficacy variables. Analyses of treatment effects were based on mean changes from baseline at 2 hours after the first and second doses of study medication. Results were analyzed using repeated measures analysis of variance.
A priori calculations using an spending function suggested that 300 subjects per group would allow 2 interim analyses and a final analysis to be performed with an overall type I statistical error of 0.05 and a power of 80%. Interim analyses were to be performed after 200 and 400 subjects had completed the study. By the time the first interim analysis was completed, rapid enrollment resulted in sufficient subjects (430) to perform the second interim analysis. Therefore, even though a sufficiently low significance level was obtained to conclude the study after the first interim analysis (P.006), the second interim analysis was performed. As would be expected, the significance value for the second interim analysis also satisfied the stopping rule (P.029) and the study was terminated. The P values from the second interim (and final) analysis are reported in the following text.
RESULTS
SUBJECTS
Four hundred thirty subjects were enrolled in the study and completed at least 1 dose of study medication; 216 received pseudoephedrine and acetaminophen, and 214 received placebo. Two hundred thirty-six subjects were enrolled at the University of Virginia, 137 at Hackensack University Medical Center, and 57 at the Medical University of South Carolina. The demographic characteristics and baseline symptom assessments for both primary and secondary efficacy variables were similar for those randomized to the treatment and placebo group (Table 1).
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Table 1. Demographic Characteristics of Subjects at Baseline Who Received Either Pseudoephedrine and Acetaminophen or Placebo
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The treatment by site interaction was not statistically significant, indicating that differences between treatment groups were stable across all 3 study sites. None of the subjects used concomitant medications, including analgesics and/or cough/cold preparations from entry into the study until after the symptom evaluation following the second dose of study medication.
Eighteen subjects, 10 (4.6%) who received pseudoephedrine and acetaminophen and 8 (3.7%) who received placebo, did not complete the study. Two subjects, both in the active treatment group, withdrew after the first dose because of adverse effects. One subject withdrew because of feeling "spacey, speedy, and shaky." The other subject experienced numbness of the legs and tremors of the right hand, symptoms she had previously experienced unrelated to the study medication. One subject who was receiving thyroid replacement for hypothyroidism was inadvertently enrolled and was withdrawn from the study following the symptom evaluation after the first dose. Seven subjects in the active treatment group and 8 subjects in the placebo group were noncompliant with the protocol. Most of these failures related to the timing of the symptom evaluations.
EFFECT OF PSEUDOEPHEDRINE AND ACETAMINOPHEN ON OVERALL SINUS SYMPTOM ASSESSMENT
The mean ± SEM sinus symptom assessment scores for the treatment and placebo groups at baseline were 2.5 ± 0 and 2.6 ± 0, respectively (P = .39). Two hours after the second dose of study medication, the mean ± SEM sinus symptom assessment score had decreased by 1.30 ± 0.06 in the active treatment group compared with 0.93 ± 0.06 in the placebo group (P<.001) (Figure 1). This reflects a reduction in the overall sinus symptom score of 51% in the pseudoephedrine and acetaminophen recipients and 36% in the placebo recipients.
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Figure 1. Comparison of the effect of pseudoephedrine hydrochloride plus acetaminophen vs placebo on perceived overall sinus symptom assessment. Assessments were made using a 5-point scale (0, absent; 1, mild; 2, moderate; 3, moderately severe; and 4, severe) after each of 2 treatment doses 6 hours apart. Data represent mean ± SEM change from pretreatment baseline. Statistical significance was determined a priori to be satisfied if P .029 at the second interim analysis.
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EFFECT OF PSEUDOEPHEDRINE AND ACETAMINOPHEN ON WEIGHTED AVERAGE OF SINUS SYMPTOMS
The mean ± SEM weighted average of sinus symptoms in the pseudoephedrine and acetaminophen and placebo groups at baseline were 2.1 ± 0.1 and 2.2 ± 0.1, respectively (P = .19). Two hours after the second dose of study medication, the mean ± SEM weighted average of sinus symptoms had decreased by 1.14 ± 0.06 in the active treatment group compared with 0.84 ± 0.06 in the placebo group (P<.001) (Figure 2). This reflects a reduction of 55% in the weighted sinus symptom score after the second dose in the pseudoephedrine and acetaminophen recipients and 39% in the placebo recipients.
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Figure 2. Comparison of the effect of pseudoephedrine hydrochloride plus acetaminophen vs placebo on the weighted average of pain, pressure, and congestion attributed to the paranasal sinuses. Assessments were made using a 5-point scale (0, absent; 1, mild; 2, moderate; 3, moderately severe; and 4, severe) after each of 2 treatment doses 6 hours apart. Data represent mean ± SEM change from pretreatment baseline. Statistical significance was determined a priori to be satisfied if P .029 at the second interim analysis.
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EFFECT OF PSEUDOEPHEDRINE AND ACETAMINOPHEN ON SECONDARY TREATMENT VARIABLES
The mean changes from baseline in symptom severity scores were significantly different for the 2 treatment groups for several of the secondary efficacy variables. Two hours after the first dose of study medication, the mean ± SEM weighted average of sinus symptoms decreased from a baseline value of 2.1 ± 0.1 by 0.85 ± 0.05 for pseudoephedrine and acetaminophen recipients compared with a decrease from a baseline value of 2.2 ± 0.1 by 0.66 ± 0.05 for the placebo recipients (P = .01) (Figure 2). This reflects a reduction of 41% in the weighted sinus symptom score after the first dose in the pseudoephedrine and acetaminophen recipients and 30% in the placebo recipients. Two hours after the first dose of study medication, the mean ± SEM overall sinus symptom assessment score had decreased from a baseline value of 2.5 ± 0 by 0.99 ± 0.06 in the active treatment recipients compared with a decrease from a baseline value of 2.6 ± 0 by 0.76 ± 0.06 in the placebo recipients (Figure 1).
Significant reductions from baseline in mean symptom scores for pseudoephedrine and acetaminophen recipients compared with placebo recipients were observed after both the first and second doses of study medication for sinus pain, sinus pressure, and headache (Table 2). The mean sinus congestion and runny nose scores were significantly reduced from baseline for pseudoephedrine and acetaminophen recipients compared with placebo recipients after the second dose of study medication (Table 2). The mean score for nasal obstruction (stopped up nose) was significantly reduced after the first dose of study medication for pseudoephedrine and acetaminophen recipients compared with placebo recipients (Table 2). While not statistically significant, there was a trend suggestive of a greater reduction in the cough score after the second dose in the active treatment group (Table 2).
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Table 2. Changes From Baseline for Nonprimary Parameter Scores in Volunteers With Colds Treated With 2 Doses of Pseudoephedrine and Acetaminophen or Placebo*
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ADVERSE EFFECTS
Fifty-one subjects (24%) in the pseudoephedrine and acetaminophen group and 25 subjects (12%) in the placebo group reported adverse effects (P = .04). Adverse effects that were judged by the blinded investigators to be related to the treatment occurred in 41 (19%) of the pseudoephedrine and acetaminophen recipients and 17 (8%) of the placebo recipients (P = .04). The difference between the 2 groups was due to the higher incidence of the following events reported by pseudoephedrine and acetaminophen recipients: nervousness (8 vs 0, P = .007), nausea (6 vs 1), dizziness (8 vs 4), dry mouth (8 vs 4), and somnolence (9 vs 5). All treatment-related adverse effects were of mild or moderate severity except for 2 cases of severe nausea in the pseudoephedrine and acetaminophen group. Two subjects, described previously, withdrew from the study because of possible adverse effects and did not receive their second dose of study medication.
COMMENT
In this 2-dose study, we looked for relief of symptoms attributed to the paranasal sinuses after the second dose of a combination of pseudoephedrine and acetaminophen. The results of the study demonstrate that this combination was effective in improving the self-reported overall sinus symptom assessment and a weighted average of specific symptoms perceived to be due to the sinuses at 2 hours after the second dose of medication.
Significant reductions were also observed following the second dose of pseudoephedrine and acetaminophen compared with placebo for the individual self-reported symptoms of sinus pain, sinus pressure, sinus congestion, runny nose, and headache. A greater reduction in symptom severity was seen at 2 hours after the second dose compared with 2 hours after the first dose. In a small study7 evaluating early treatment, subjects with induced rhinovirus colds who received pseudoephedrine plus ibuprofen starting 30 hours after virus challenge had significantly reduced nasal congestion scores compared with placebo recipients. Subjects who received pseudoephedrine alone had reduced total systemic symptom scores, which included headache, and they required less acetaminophen for headaches than subjects receiving placebo.
Changes in the sinuses are apparent early in the course of the common cold. Of 31 adults with natural colds who underwent computed tomographic scanning, 87% had abnormalities in the maxillary sinuses, 65% had abnormalities of the ethmoid sinuses, 32% had abnormalities of the frontal sinuses, and 39% had abnormalities of the sphenoid sinuses.3 Occlusion of the ethmoid infundibulum was observed in 77%. Subjects with sinus abnormalities and those with infundibular occlusion were more likely to have engorged turbinates and mucosal thickening of the nasal wall than subjects without sinus abnormalities. The frequency of abnormalities of the sinuses or occlusion of the ethmoid infundibulum was higher in those subjects with colds who reported nasal or head congestion than in subjects with colds who did not report congestion.
The pathophysiologic changes leading to the perception of discomfort attributed to the sinuses, including whether these symptoms are actually due to sinus involvement, are not well understood. Cavernous plexuses, venous networks with arteriovenous anastomoses, are best developed over the inferior and middle nasal turbinates, as well as near the openings of the paranasal sinuses. Reduction in clearing of nasal discharge may occur as a result of changes in blood volume in these plexuses. The vasculature is under sympathetic and parasympathetic control. The beneficial effects of pseudoephedrine and acetaminophen on symptoms observed in the present study probably relate to both the decongestant activity of pseudoephedrine on these plexuses as well as the analgesic effect of acetaminophen. Sensitive reverse transcription polymerase chain reaction assays have recently detected rhinovirus in the maxillary aspirates of 8 (40%) of 20 adults with acute community-acquired sinusitis,2 suggesting that viral infection of the sinuses may predispose subjects to sinus symptoms and that the common cold is a viral rhinosinusitis.3, 14
Acute bacterial sinusitis has been reported to occur as a sequelae to 0.5%15 to 5.0%16 of colds. We did not specifically address whether early decongestant treatment of persons with these symptoms would reduce the incidence of acute bacterial sinusitis; such a study would have required very large sample sizes. If subjects who are at increased risk for the development of bacterial sinusitis can be identified, future studies might be powered to examine the effect of various therapeutic interventions on preventing secondary bacterial infections. Also of importance and worthy of further study is whether early therapy of sinus symptoms with over-the-counter remedies will reduce physician visits and the inappropriate use of antibiotics for empiric treatment of cold and sinus symptoms.
The study design employed in this trial differed from some prior studies in that symptom assessments were made following each of 2 doses of study medication over an 8-hour period. Relief was specifically sought following the second dose rather than as a daily assessment of symptoms continuing for several days. The brief observation period had the potential to enhance compliance. It was determined a priori that the primary end point for the efficacy variables would be 2 hours following the second dose of medication; statistically significant differences between the treatment groups were observed at the time of the interim analyses, which was also determined a priori.
Adverse effects believed to be related to the study medication occurred twice as frequently among recipients of pseudoephedrine and acetaminophen and were generally consistent with those attributed to an oral sympathomimetic agent. For the most part these were of minor clinical significance, but caution should be exercised in extrapolating these results to persons with underlying medical conditions, as our study population comprised previously healthy individuals. Based on the results of this study, the combination of pseudoephedrine plus acetaminophen is an effective and well-tolerated combination for relief of symptoms attributed to the paranasal sinuses that develop early in the course of the common cold.
AUTHOR INFORMATION
Accepted for publication July 12, 2000.
This study was supported in part by Novartis Consumer Health Inc (formerly Sandoz Pharmaceuticals Corp, Consumer Division), Summit, NJ.
This study was presented in part at the 36th Annual Meeting of the Infectious Diseases Society of America, Denver, Colo, November 12-15, 1998. Abstract No. 306.
Informed consent was obtained from all subjects who participated in this study, and the guidelines for human experimentation of the US Department of Health and Human Services and those of the institutions where the study was conducted were followed in the conduct of this study.
We thank the study nurses for this trial for their valuable contributions: Pat Beasley, RN, and Kathy Adams, RN, University of Virginia, Charlottesville; Tami Crupi, RN, and Alison Stiroh, RN, Hackensack University Medical Center, Hackensack, NJ; and Genny Connelly, BSN, Medical University of South Carolina, Charleston. The authors also thank Marie Balsamello for assistance with manuscript preparation.
Editor's Note
I personally have avoided over-the-counter medications for my colds, primarily because it seems the side effects outweigh any modest improvement in the natural symptoms of the cold. When considering sales figures, it is obvious that many Americans disagree with me. This study indicates statistically significant improvement in sinus symptoms of a common cold when treated with the combination of pseudoephedrine and acetaminophen compared with placebo, with a greater response after the second rather than the first dose. However, the difference in the average improvement between the active drug and placebo was on the order of 0.3 on a 5-point scale; the placebo itself was associated with an improvement of about 0.6 to 1.0 on the 5-point scale. In return, about 1 in 5 patients receiving active treatment noted side effects compared with 1 in 10 of the patients receiving placebo. While the balance of these 2—benefit vs side effect—can vary between individuals, one wonders if the money would be better spent elsewhere.—Marjorie A. Bowman, MD, MPA
Reprints: Steven J. Sperber, MD, Infectious Diseases Division, Hackensack University Medical Center, 20 Prospect Ave, Suite 507, Hackensack, NJ 07601 (e-mail: ssperber{at}humed.com).
From the Department of Internal Medicine, Hackensack University Medical Center, Hackensack, NJ, and the University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark (Dr Sperber); Departments of Pediatrics and Laboratory Medicine, Medical University of South Carolina, Charleston (Dr Turner); Healthcare Products Development, Norwalk, Conn (Dr Sorrentino); Novartis Consumer Health Inc, Summit, NJ (Mr O'Connor); SCIREX Corp, Bloomingdale, Ill (Dr Rogers); Department of Internal Medicine, University of Virginia School of Medicine, Charlottesville (Dr Gwaltney).
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